The present invention is concerned with a novel process for making a compound of formula ##STR3## wherein R signifies a C.sub.1-23 -alkyl group or a C.sub.2-23 -alkenyl group (as defined in more detail hereinafter), by the enzyme-catalyzed, selective monoacylation of a compound of formula ##STR4## The compounds of formula I, (11Z,13Z)-7,10-dihydro-10-hydroxy-retinyl acylates (2Z,4Z,7E)-carboxylic acid 3,7-dimethyl-6-hydroxy-9-2',2',6'-trimethyl-cyclohex-6'-en-1'-yl!nona-2,4 ,7-trienyl esters!, are starting materials used for making the corresponding vitamin A acylates, namely by cleavage of water and simultaneous cis-trans isomerization, which can be carried out in a manner known per se. Using the usual standard esterification methods there is obtained, for example, by acetylating the compound of formula II (11Z,13Z)-7,10-dihydro-10-hydroxy-retinol, otherwise named (2Z,4Z,7E)-3,7-dimethyl-9-2',2',6'-trimethyl-cyclohex-6'-en-1'-yl!nona-2, 4,7-trien-1,6-diol! in addition to the desired and especially important compound of formula I wherein R is methyl, i.e. (11Z,13Z)-7,10-dihydro-10-hydroxy-retinyl acetate, also the byproduct compound (11Z,13Z)-7,10-dihydro-10-acetoxy-retinyl acetate (2Z,4Z,7E)-acetic acid 6-acetoxy-3,7-dimethyl-9-2',2',6'-trimethyl-cyclohex-6'-en-1'-yl!nona-2,4 ,7-trienyl ester! of formula ##STR5## which occurs in varying amounts.
The (11Z,13Z)-7,10-dihydro-10-acetoxy-retinyl acetate of formula III is inert under the conditions of the catalytic dehydration and is therefore troublesome not only in the working-up of the compound of formula I, in which R signifies methyl (11Z,13Z)-7,10-dihydro-10-hydroxy-retinyl acetate!, but also in the working-up of vitamin A acetate. Accordingly, a process not only for the selective monoacetylation, but also generally for the selective monoacylation of a compound of formula II (11Z,13Z)-7,10-dihydro-10-hydroxy-retinol! so as not to form diacylated byproducts, such as the compound of formula III, is of great interest.
An object of the present invention is to provide a process for making the compounds of formula I (11Z,13Z)-7,10-dihydro-10-hydroxy-retinyl acylates! by the esterification of a compound of formula II (11Z,13Z)-7,10-dihydro-10-hydroxy-retinol! which does not have the disadvantages of previously known procedures (e.g. undesired formation of the compound of formula III, (11Z,13Z)-7,10-dihydro-10-acetoxy-retinyl acetate. Thus, it is necessary that the process proceeds extremely selectively and in high yields, and that the material used to esterify the compound of formula II displays catalytic activity even in low amounts, can be readily separated and can be used again several times.
The selective acylation of primary hydroxy groups in addition to secondary in the presence of lipases is known from the literature. Thus, for example, according to J. Org. Chem. 55, 2366-2369 (1990) the acylation of amphenicols, i.e. of phenyl-substituted short-chain aliphatic diols, by esterification with a trifluoroethyl acylate or a cyclic anhydride is carried out using a lipase isolated from Pseudomonas cyclopium, with the yields being 83% and 64%, respectively, without the purity being given.
The racemate resolution of 2-methyl-5-(4-methoxyphenyl)pentane-1,3-diol by esterification with vinyl acetate in the presence of immobilized lipase PS is described in Tetrahedron: Asymmetry 4, 757-760 (1993), with the yield of monoacylated product being 66% and the optical purity being 42% e.e.
In Appl. Biochem. Biotechnol. 11, 401-407 (1985) a series of 1,2- and 1,3-diols (dissolved in ethyl acylates) has been acylated with lipase from porcine pancreas in yields of .ltoreq.97%.
According to J. Chem. Soc., Chem. Commun., 1989, 1535-1536, 2-ethyl-hexane-1,3-diol has been acylated with lipase from porcine pancreas in 60% yield.
Tetrahedron Lett. 31, 3405-3408 (1990) describes the selective acylation of aliphatic 1,n-diols with anhydrides in the presence of lipase from porcine pancreas, with the selectivities being .ltoreq.98% and the yields being .ltoreq.95%.
The selective acylation (98% selectivity) of 1,5-hexanediol with n-decanoic acid with lipase from Chromobacterium viscosum is described in Ind. J. Chem. 32, 30-34 (1993).
All of these previously known processes have certain disadvantages: thus all of these processes yield the desired products, but the selectivity and therewith the purity and/or the yield leave much to be desired. Moreover, none of these literature references mentions a repeated use of the lipase employed, i.e. the stability of the lipase, let alone a simultaneous substrate purification.
In the scope of the present invention the above-mentioned object of selective and high yield acylation with a material featuring high catalytic activity, ready separability and reuseability has been achieved by carrying out the acylation of the compound of formula II (11Z,13Z)-7,10-dihydro-10-hydroxy-retinol! with an acylation agent in the presence of a lipase (enzyme class EC 3.1.1.3) to form the compound of formula I an appropriate (11Z,13Z)-7,10-dihydro-10-hydroxy-retinyl acylate! under a variety of specific pre-reaction and reaction conditions.